Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours

Abstract Background The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. Methods A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002–2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). Results A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). Conclusions Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.


Introduction
Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) have historically been considered rare neoplasms, but their incidence has significantly risen over the past two decades due to the widespread use of high-quality imaging techniques 1 .NF-PanNETs encompass a heterogenous group of lesions with varying biological behaviours, ranging from indolent to highly aggressive tumours 2 .Risk stratification of NF-PanNETs heavily relies on postoperative histopathological features.Tumour stage, grade, necrosis, perineural and microvascular invasion have emerged as the most relevant prognostic factors in patients undergoing surgery for NF-PanNETs [3][4][5][6] .However, the availability of preoperative predictors of aggressiveness remains limited [7][8][9][10][11] .Consequently, achieving appropriate and tailored management of these neoplasms poses a significant challenge.
Surgery represents the mainstay of curative treatment for localized NF-PanNETs 12,13 .Despite the high curative rates associated with surgical resection, approximately 15-30% of patients experience disease recurrence within 5 years from surgery [14][15][16][17] .Given these findings, surgeons must carefully evaluate the risks associated with treatment decisions.In certain patients, surgery may represent a futile intervention, prompting consideration of multimodal treatment approaches to minimize the risk of early recurrence.Conversely, in other cases, a non-operative treatment may be a more appropriate therapeutic choice, particularly for patients with lesions before surgery deemed to have a low risk of aggressiveness.Indeed, recent studies [18][19][20] have evaluated and confirmed the safety of 'active surveillance' as an alternative to surgical resection for patients affected by sporadic, small, asymptomatic NF-PanNETs.Thus, in the presence of specific clinico-radiological features, surgery may constitute overtreatment, subjecting patients to an unnecessary and potentially harmful procedure.Notably, pancreatic surgery carries a risk of high perioperative morbidity BJS Open, 2024, zrae083 https://doi.org/10.1093/bjsopen/zrae083Original Article rate, including major complications 21,22 as well as long-term pancreatic functional impairment 23 .
The aims of this study were to: i) evaluate the appropriateness of surgical treatment in patients undergoing surgery for NF-PanNETs and ii) investigate the preoperative features predicting the likelihood of exposing the patients to potential overtreatment or potential undertreatment in this setting.

Study design
The present retrospective observational study adhered to the STROBE guidelines 24 .All consecutive patients who underwent potentially curative surgery (R0-R1) for NF-PanNETs at San Raffaele Hospital (Milan, Italy) from November 2002 to March 2022 were considered.Exclusion criteria encompassed patients under the age of 18 years, patients with functioning neoplasms and individuals diagnosed with poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs).Palliative tumour resection (R2) cases were also excluded.The flow of patients from initial screening to the final study sample is depicted in Fig. S1.Given the retrospective nature of the study, ethical committee approval was not required.

Definition of surgical treatment appropriateness
The appropriateness of surgical treatment was categorized into three groups: potential overtreatment, appropriate treatment and potential undertreatment, based on final histologic findings and occurrence of disease relapse within 1 year following surgery.
Radical resection (R0/R1 resection) was achieved in all patients across the three categories, including in the presence of distant metastases.
The potential overtreatment group included patients who underwent radical surgical resection but had no histologic evidence of tumour aggressiveness (that is G1, T1-T2, N0, M0, no microvascular and/or perineural invasion) and did not experience disease recurrence.
The appropriate surgical treatment group included patients who underwent radical surgical resection and had histologic evidence of at least one feature of aggressiveness (that is G2-G3, T3-T4, N1, M1, microvascular or perineural invasion) but did not experience disease recurrence within 1 year following surgery.
The potential undertreatment group comprised patients who underwent radical surgical resection and experienced disease recurrence within 1 year from surgery.

Data collection
A comprehensive collection of preoperative, intraoperative and postoperative data was conducted by retrospectively retrieving information from a prospectively maintained institutional database.Preoperative variables, including demographic characteristics (age and sex), body mass index (BMI) and presenting symptoms were reviewed.Performed diagnostic procedures, including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and 68 Gallium positron emission tomography ( 68 Ga-PET), were documented, along with the radiological tumour site (head/ uncinate process versus body/tail) and size (maximum diameter assessed by imaging techniques).The date of surgery was categorized into four surgical time intervals (2002-2007,  2008-2012, 2013-2017, 2018-2022) for analysis.Intraoperative parameters included the type of surgery (pancreatoduodenectomy, distal pancreatectomy, total pancreatectomy, enucleation, middle pancreatectomy), surgical approach (laparoscopic versus open) and vascular resection.The duration of hospital stay (LOS) was calculated from the date of surgery to the date of discharge.Postoperative complications were classified according to the Clavien-Dindo classification of surgical complications 25 .Postoperative pancreatic fistula (POPF) was graded according to the 2016 definition proposed by the International Study Group on Pancreatic Surgery (ISGPS) 26 .Long-term pancreatic impairment (endocrine and/or exocrine insufficiency) occurring after surgery was also recorded.Tumour grade was determined based on the 2017 World Health Organization (WHO) classification into G1 (Ki67 < 3%), G2 (Ki67 3-20%) and G3 (Ki67 > 20%) 27 .The Ki67 proliferative index was assessed by MIB1 antibody staining and expressed as the percentage of cells with nuclear staining in 2000 cells, counted in the area of highest nuclear labelling 28 .Tumour stage was categorized following the current European Neuroendocrine Tumour Society (ENETS) TNM staging system 29 .The status of the surgical margins was evaluated and classified as R0 (no residual tumour) and R1 (microscopic residual tumour).R1 resection was defined as the presence of microscopic residual tumour at the resection margins, or in the presence of a minimum margin length ≤1 mm.Additionally, the presence of microvascular invasion, perineural invasion and necrosis was reviewed.

Definition of survival outcomes
Disease-free survival (DFS) was defined as the time from surgery to any kind of disease recurrence.Overall survival (OS) was calculated as the time from surgery to the date of death for any cause, and censored.Disease-specific survival (DSS) was defined as the time from surgery to disease-related death.DFS, OS and DSS were censored at the last follow-up.

Statistical analysis
Categorical variables were presented as absolute numbers with corresponding percentages, and compared using the χ 2 or Fisher's exact test, as appropriate.Continuous variables were reported as median with interquartile ranges (i.q.r.) for skewed distribution, or as mean (s.d.) for normal distributions.The normality of continuous variables was assessed using the Kolmogorov-Smirnov test.Continuous variables were compared between two groups by using the Student's t test or Mann-Whitney U test, as appropriate based on the distribution of the variables.The Kruskal-Wallis test was performed to compare continuous variables between multiple groups.Bonferroni correction was applied to account for multiple comparisons, both for categorical and continuous variables.Receiver operating characteristic (ROC) curve analysis was performed to evaluate radiological tumour size as a predictor of treatment appropriateness and to find the best cut-off to identify patients at higher risk of overtreatment before surgery.The global performance was expressed as area under the curve (AUC).Multivariable logistic regression analysis was performed to identify preoperative predictors of potential surgical overtreatment and undertreatment.Only variables that exhibited significant associations with treatment appropriateness in the univariate analysis were included in the initial multivariable model.A backward stepwise selection procedure was employed to derive the final multivariable model.When necessary, continuous variables were categorized based on their median value.
Survival probability was estimated using the Kaplan-Meier method.The log-rank test was employed to compare DFS, OS and DSS among the potential overtreatment, potential undertreatment and appropriate treatment groups.Statistical significance was set at a P value less than 0.05.All statistical analyses were performed using SPSS version 26.0 for Mac software (SPSS, Inc., Chicago, IL, USA).
An increase in the rate of appropriately treated patients has been observed after the introduction of institutional multidisciplinary meetings (2018), with a concurrent decrease in  Patients with tumours located in the pancreatic body-tail exhibited a significantly higher frequency of potential overtreatment (39%, 98 of 253) compared with patients with pancreatic head lesions (31 of 131, 24%; P = 0.012).Furthermore, a smaller radiological diameter was significantly associated with potential overtreatment (potential overtreatment: 20 mm (i.q.r.15-27), appropriate treatment: 30 mm (i.q.r.24-47), potential undertreatment: 34 mm (i.q.r.30-64); P < 0.001).By ROC curve analysis (Fig. S3), a radiological tumour size of 25.5 mm was identified as the most accurate cut-off, demonstrating 71% sensitivity and 74% specificity in predicting potential overtreatment.The global performance of tumour radiological diameter as a predictor of potential overtreament was deemed adequate (AUC 0.783, 95% c.i. 0.736 to 0.830, P 0.001).
The type of surgical intervention was significantly associated with treatment appropriateness (P < 0.001).

Discussion
This study investigated the appropriateness of surgical treatment and associated factors in patients with resectable NF-PanNETs.Surgery for NF-PanNETs presents numerous challenges due to the unique biological behaviour of these tumours.The inherent heterogeneity in aggressiveness poses a significant risk of inadequate surgical resection, resulting in both potential overtreatment and futile interventions.
The current study investigated the suitability of surgical management in a large, single-institution series of 384 patients submitted to curative surgery for NF-PanNET at a tertiary referral centre.The decision to proceed with surgery was found to be appropriate in the majority of patients (60%), nevertheless a significant proportion of cases of potential overtreatment and of futile resection was identified.The rate of potentially overtreated cases decreased over time, which may be attributed to the evolution in the management of small, asymptomatic NF-PanNETs as well as to the advancement in imaging techniques allowing enhanced characterization and identification of these lesions.Indeed, recent studies have shown the feasibility and safety of a 'watch and wait' approach for asymptomatic sporadic NF-PanNETs ≤ 2 cm 18,19,30 , leading to a reduction in the risk of overtreatment.Moreover, the current study revealed that patients who underwent surgical resection before 2015 were more likely to experience potential overtreatment.This finding can be attributed to the publication of the ENETS 13 consensus guidelines in 2016, which recommended conservative management instead of a surgical approach for this particular subset of patients.These guidelines likely influenced clinical practice and led to a shift in the management of small, asymptomatic NF-PanNETs.Furthermore, the introduction of institutional multidisciplinary meetings in 2018 has likely contributed to the increase in the rate of patients receiving appropriate treatment, ensuring a comprehensive assessment of patients' management.Nevertheless, the rate of cases receiving potential undertreatment remained stable over the study interval, indicating that there have been no significant advances in the management of localized aggressive lesions in the past 20 years.Patients experiencing early disease relapse after surgery might benefit from multimodal treatment approaches.A previous small series reported promising results in this setting, indicating improved oncological outcomes when patients underwent sequential treatments such as surgery preceded by peptide receptor radionuclide therapy [31][32][33] .However, larger and more rigorous studies are needed to validate the effectiveness of perioperative medical treatments in this specific context.
The findings of the current study, which identified small tumour diameter and pancreatic body/tail location as independent predictors of potential overtreatment, as well as radiological tumour size as a preoperative determinant of potential undertreatment, are consistent with several prior reports in the literature [3][4][5][6] .Previous studies 18,20 have highlighted the challenge of appropriately managing small tumours, particularly those located in the pancreatic body/tail.Importantly, the current study identified a diameter of 25.5 mm as the optimal cut-off for preoperative assessment, effectively distinguishing patients at high risk of overtreatment.This finding implies that patients with tumours smaller than 25.5 mm should undergo careful evaluation before making treatment decisions.Indeed, such patients could be suitable candidates for active surveillance or potentially benefit from a parenchyma-sparing resection approach.
Furthermore, it is reasonable to speculate that the observed correlation between tumour location and potential overtreatment may be attributed to the fact that surgical resections for tumours situated in the pancreatic body/tail (that is distal pancreatectomy) are comparatively less technically challenging and associated with lower postoperative morbidity rates, in contrast to resections required for pancreatic head lesions (that is pancreatoduodenectomy) 34 .Consequently, surgeons may be more inclined to opt for surgical intervention in cases involving pancreatic body-tail lesions, even in the absence of clear preoperative indications of aggressiveness.
Another notable finding from this study pertains to the detrimental consequences of potential unnecessary surgical interventions.Noteworthy is the rate of postsurgical morbidity among potentially overtreated patients, which has significant implications.Alarmingly, the current results indicate that 25% of potentially overtreated patients experienced postoperative pancreatic impairment, consequently impairing their quality of life 23,35,36 .In addition, potentially undertreated patients showed lower overall survival compared with those reported in the literature for patients undergoing curative surgery for locally advanced 37 and metastatic 38,39 PanNETs.
The current study has several limitations that should be recognized.The first one is related to its retrospective design.Second, a referral bias might be present, as only patients submitted to surgery in a tertiary centre were considered in this series.Moreover, surgical outcomes were not compared with those of non-operative control groups, which does not allow for the validation of the patients' classification.In addition, variables such as tumour growth and patients' choice could not be included in the analysis, thereby precluding an assessment of their impact on surgical indications.Finally, the study developed over a long interval, during which significant evolutions in PanNETs assessment and management as well as advances in surgical techniques occurred.
In conclusion, the study provides insights into the treatment appropriateness for surgically managed NF-PanNETs over a 20-year interval.Potential overtreatment remains a concern, but the rate of appropriately treated patients has been increasing.Surgeons could enhance their clinical judgment and tailor treatment approaches to improve treatment selection, especially in the presence of tumours located in the pancreatic body-tail and/or with a radiological diameter < 25.5 mm.Further research is needed to increase current ability to predict tumour aggressiveness before surgery.

Fig. 1
Fig. 1 Patients who underwent surgery for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) and received potential overtreatment, appropriate treatment or potential undertreatment

Fig. 2
Fig. 2 Comparison of rates of potential overtreatment, appropriate treatment and potential undertreatment between patients who underwent surgery for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) over the study interval (2002-2022), categorized into four subintervals

Table 1 Comparison of demographics, clinical and preoperative characteristics between patients who underwent surgery for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) and received potential overtreatment (n = 129), appropriate treatment (n = 230) and potential undertreatment (n = 25) Variable Potential overtreatment n = 129 Appropriate treatment n = 230 Potential undertreatment n = 25 Overall P* Adj. P † PO versus AT Adj. P ‡ PO versus PU Adj. P § AT versus PU
Values are n (%) unless otherwise indicated.Values in bold indicate statistical significance.BMI, body mass index; CT, computed tomography; MRI, magnetic resonance; PET, positron emission tomography; EUS, endoscopic ultrasound; Adj, adjusted; PO, potential overtreatment; AT, appropriate treatment; PU, potential undertreatment.* Potential overtreatment versus appropriate treatment versus potential undertreatment.† Potential overtreatment versus appropriate treatment, P values with Bonferroni correction for multiple comparisons.‡ Potential overtreatment versus potential undertreatment, P values with Bonferroni correction for multiple comparisons.§ Appropriate treatment versus potential undertreatment, P values with Bonferroni correction for multiple comparisons.